PROJECT 3 SUMMARY African American/black (AA) men have a higher overall incidence, earlier age of onset, increased proportion of clinically advanced disease, and increased mortality from prostate cancer (PCa) compared to European Americans (EA). These differences persist even after correcting for socioeconomic covariates. This raises the possibility that ancestral differences in PCa biology or somatic genetics might contribute at least in part to the observed differences in outcome. We have recently completed whole exome sequencing characterization of primary prostate cancer from African American men and identified potential genomic differences between prostate cancers in AA men and men of European ancestry. These data as well as work from others suggest that underlying genomic alterations may be contributing to disparities in prostate cancer outcomes among AA men. We hypothesize that 1) African American/black (AA) prostate cancers harbor distinct genomic alterations that correlate with resistance to androgen-directed therapies and may contribute to the poorer outcomes observed in AA men with prostate cancer compared to their European counterparts; and that 2) aggressive prostate cancers have distinct cellular composition in the microenvironment compared to less aggressive cancers in AA men. Our goal is to leverage genomic technologies to identify the genomic alterations and cellular populations that are associated with lethal prostate cancer in men of African ancestry. To achieve this goal, we propose the following specific aims: 1) To determine the genomic alterations in plasma cell-free DNA (cfDNA) associated with resistance to androgen- directed therapies in men of African ancestry with mCRPC and 2) To characterize the cancer and immunological cellular subpopulations associated with aggressive primary prostate cancers in men with African ancestry using single-cell RNA sequencing. The results of this project will advance our understanding of the genomic and cellular features that are associated with lethal and aggressive prostate cancers in men of African ancestry.